title: A possible simplification for the estimation of area under the curve (AUC₀₋₁₂) of enteric-coated mycophenolate sodium in renal transplant patients receiving tacrolimus.
abstract: Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplantation. With a delayed absorption profile, it has not been possible to develop limited sampling strategies to estimate area under the curve (mycophenolic acid [MPA] AUC₀₋₁₂), which have limited time points and are completed in 2 hours. We developed and validated simplified strategies to estimate MPA AUC₀₋₁₂ in an Indian renal transplant population prescribed EC-MPS together with prednisolone and tacrolimus. Intensive pharmacokinetic sampling (17 samples each) was performed in 18 patients to measure MPA AUC₀₋₁₂. The profiles at 1 month were used to develop the simplified strategies and those at 5.5 months used for validation. We followed two approaches. In one, the AUC was calculated using the trapezoidal rule with fewer time points followed by an extrapolation. In the second approach, by stepwise multiple regression analysis, models with different time points were identified and linear regression analysis performed. Using the trapezoidal rule, two equations were developed with six time points and sampling to 6 or 8 hours (8hrAUC[₀₋₁₂exp]) after the EC-MPS dose. On validation, the 8hrAUC(₀₋₁₂exp) compared with total measured AUC₀₋₁₂ had a coefficient of correlation (r²) of 0.872 with a bias and precision (95% confidence interval) of 0.54% (-6.07-7.15) and 9.73% (5.37-14.09), respectively. Second, limited sampling strategies were developed with four, five, six, seven, and eight time points and completion within 2 hours, 4 hours, 6 hours, and 8 hours after the EC-MPS dose. On validation, six, seven, and eight time point equations, all with sampling to 8 hours, had an acceptable r with the total measured MPA AUC₀₋₁₂ (0.817-0.927). In the six, seven, and eight time points, the bias (95% confidence interval) was 3.00% (-4.59 to 10.59), 0.29% (-5.4 to 5.97), and -0.72% (-5.34 to 3.89) and the precision (95% confidence interval) was 10.59% (5.06-16.13), 8.33% (4.55-12.1), and 6.92% (3.94-9.90), respectively. Of the eight simplified approaches, inclusion of seven or eight time points improved the accuracy of the predicted AUC compared with the actual and can be advocated based on the priority of the user.
authors.affiliation: Clinical Pharmacology Unit, Christian Medical College, Vellore, Tamil Nadu, India. clinpharm@cmcvellore.ac.in
authors.forename: Denise H
authors.initials: DH
authors.lastname: Fleming
authors.forename: Binu S
authors.initials: BS
authors.lastname: Mathew
authors.forename: Samuel
authors.initials: S
authors.lastname: Prasanna
authors.forename: Vellaichamy M
authors.initials: VM
authors.lastname: Annapandian
authors.forename: George T
authors.initials: GT
authors.lastname: John
mesh_terms: D019540:Area Under Curve; D003692:Delayed-Action Preparations; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D009173:Mycophenolic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011239:Prednisolone / Q000627:therapeutic use; D015203:Reproducibility of Results; D013608:Tablets, Enteric-Coated; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus